1-amino-alkylcyclohexane derivatives for the treatment of inflammatory skin diseases

ABSTRACT

The present invention relates to the treatment of an individual afflicted with inflammatory skin diseases comprising administering to the individual an effective amount of a 1-amino-alkylcyclohexane derivative.

FIELD OF THE INVENTION

The present invention relates to the treatment of an individualafflicted with inflammatory skin diseases, comprising administering tothe individual an effective amount of a 1-amino-alkylcyclohexanederivative.

BACKGROUND OF THE INVENTION

This invention relates to methods of treating patients afflicted withinflammatory skin diseases, including acne, rosacea, eczema, atopicdermatitis, psoriasis and oily skin.

Acne is the most common skin disease. Epidemiologic data suggest that upto 80% of individuals may be affected. Men and women develop acne aboutequally, and the onset of the disease typically occurs at age 10-14years and regresses by age 20-25 years. In some patients acne persistsinto fourth or fifth decade of life (persistent acne). The clinicalspectrum of acne ranges from mild manifestations (e.g., a few comedones(acne lesions) with occasional inflamed papulopustules to “clinical”acne in more severe cases) to severe inflammation and abscess formationon the face or upper trunk. Follicular rupture may follow leading to aforeign body reaction including abscesses, fistulas and systemic signsof inflammation (acne conglobata).

Increased sebum production, which is believed to be regulated byandrogens is thought to be one of the main causes of acne (seborrhea)development. A further prerequisite for developing acne is a disturbedfollicular keratinisation leading to hyperkeratosis. Factors responsiblefor follicular hyperkeratosis include the following: localized,follicular linolic acid deficiency, comedogenic sebum components,changes in the lipid composition of sebum, bacterial metabolites andmediators of inflammation.

Propionibacteria (Propionibacterium acnes) are the dominant bacteria inhair follicles. These bacteria prefer micro-aerobic or anaerobicconditions and preferentially colonize regions with high sebumproduction. A four log higher concentration of propionibacteria is foundin 11-20 year olds with acne compared to 11-20 year olds without acne.Bacterial lipases release irritative and pro-inflammatory free acids andother potentially pro-inflammatory bacterial metabolites such asproteases, hyaluronidases and chemotactic factors. Metabolites ofpropionibacteria induce follicular and perifollicular inflammation,especially due to chemotactic substances. Other immunological andinflammatory factors play also a role in the development and course ofacne (e.g., toll-like receptor 2, IL-1, IL-8, LTB4, PPAR alpha).

There are a number of topical as well as systemic treatment optionsavailable for acne. Topical treatments for acne include: Retinoids,which normalise follicular keratinisation; Benzoylperoxide (BPO), whichis an anti-bacterial agent that reduces Propionibacterium acnes (P.acnes) within the follicle; and topical antibiotics with anantibacterial effect. Systemic treatment options for acne includeantibiotics. Systemic treatment options also include hormones for femalepatients.

Rosacea is a common, chronic cutaneous inflammatory disease, primarilyof the facial skin. It is common in the third and fourth decade of life,peaking at the age of 40 and 50 years. The causes of rosacea have notyet been identified. Facial vascular reactivity, dermal connectivetissue structure or composition, pilosebeaceous structure, microbialcolonization and a combination of factors that alter the cutaneousresponse to rosacea trigger factors, respectively, are seen as majorpathogenic mechanisms. Important trigger factors among others appear tobe hot or cold temperature, sunlight, wind, hot drinks, spicy food,alcohol, exercise, emotions, and topical irritants which lead toflushing and blushing. Early stage rosacea is characterized bypersistent erythema and teleangiectasia, predominantly of the cheeks,frequently followed by papules and papulopustules. In later stages,diffuse hyperplasia of connective tissue and sebaceous glands may occur.This can cause a hypertrophy of the nose, a so-called rhinophyma.Rosacea occurs in stages and may affect the eyes, most commonlyresulting in blepharitis and conjunctivitis. Rosacea may occur in areasother than the face, such as retroauricular areas, as well as on theneck, chest, back and scalp. The clinical appearance of rosacea may besimilar to acne, but, in contrast, rosacea is not a primary folliculardisease.

Oral tetracycline antibiotics, such as tetracycline, doxycycline, andminocycline, and topical antibiotics, such as metronidazole, which areused in acne, are also a treatment option for rosacea and are used torelieve papules, pustules, inflammation and some redness.

Eczema is a general term encompassing various inflamed skin conditionssuch as atopic dermatitis, allergic contact dermatitis and occupationaldermatitis.

Atopic dermatitis is a pruritic that typically starts in early infancy(although an adult-onset variant is recognized). Atopic dermatitis ischaracterized by pruritus, eczematous lesions, xerosis (dry skin), andlichenification (thickening of the skin and an increase in skinmarkings).

Atopic dermatitis results from complex interactions between geneticsusceptibility genes resulting in a defective skin barrier, defects inthe innate immune system, and heightened immunological responses toallergens and microbial antigens. The dysfunction of the barrier iscaused by downregulation of cornified envelope genes (fillagrin andloricrin), reduced ceramide levels, increased levels of endogenousproteolytic enzymes, and enhanced transepidermal water loss. Disturbanceof the barrier may also be caused by soaps and detergents and/or byexposure to exogenous proteases from house dust mites and Staphylococcusaureus. This is worsened by the lack of certain endogeneous proteaseinhibitors in atopic skin. These epidermal changes likely contribute toincreased allergen absorption into the skin and microbial colonization.Current thinking is that microbial superantigens play a major role; theycan more easily penetrate into the viable skin layers via the disturbedbarrier and induce an influx of T cells (predominantly activated memoryT cells suggesting previous encounter with antigen) with occasionalmacrophages.

Pruritus is a prominent feature of atopic dermatitis, manifested ascutaneous hyperreactivity and scratching following exposure toallergens, changes in humidity, sweating, and low concentrations ofirritants. The mechanisms of pruritus are poorly understood; however, itis believed that inflammatory cells play an important role. There is anitch-scratch cycle. Repetitive scratching activates areas in theprefrontal cortex and orbifrontal cortex. This may explain the hedonicand compulsive components of scratching and may be associated withrelease of endogenous opioids. Repetitive scratching in atopicdermatitis causes secretion of neuropeptides and opiates that mayfurther augment the vicious itch-scratch cycle.

Psoriasis is a polygenetic hereditary multifactor inflammatory skindisease of unknown pathogenesis, which may be influenced by a number ofenvironmental factors. There is a strong genetic basis leading tocomplex alterations in epidermal growth and differentiation and multiplebiochemical, immunological, and vascular abnormalities, and a poorlyunderstood relationship to nervous system function. The pathogenesis ofpsoriasis is rather complex involving local and systemic factors. Atpresent, the abnormal epidermal hyperproliferation is regarded as asecondary phenomenon following T-lymphocyte mediated autoimmunereaction. It has also been reported that immunological reaction toStreptococcus species may also play a role. Epidermal proliferation inlesional skin is characterized by increased recruitment of cycling cellsfrom the resting GO population. In contrast to older data, cell cycletimes in the psoriatic lesion are essentially normal. In particular, thesuprabasal compartment is characterized by expression of molecules thatare absent or have restricted expression in normal skin. In primarykeratinocyte cultures, soluble factors from CD4+ T-lymphocyte clonesderived from psoriatic plaques promote proliferation of the psoriaticCD29+ keratin-10 subpopulation, whereas CD29+ keratin-10 keratinocytesfrom normal subjects failed to have such a growth response to solublefactors from the same T cell clones. This suggests that a subpopulationof epidermal cells derived from psoriatic plaques do respond abnormallyto T-lymphocyte clones from psoriatic plaques.

Oily skin is due to excessive sebum production by sebaceous glands.Excessive sebum production may be caused by hormonal imbalances duringpregnancy and menopause, heredity, diet, birth control pills, cosmeticsuse or humidity and hot weather or diseases such as Morbus Parkinson.

Excess sebum produces surface oiliness, blocks pores, providesnourishment to bacteria that live upon the skin (P. acnes) andcontributes to acne flare-ups.

Impetigo contagiosa is a superficial bacterial skin infection mostcommon among school children. People who play close contact sports suchas rugby and wrestling are also susceptible, regardless of age. Impetigois not as common in adults. It is highly contagious and also known asschool sores. It is primarily caused by Staphylococcus aureus and byStreptococcus pyogenes. Impetigo generally appears as honey-coloredscabs formed from dried serum, and is often found on the arms, legs, orface. The infection is spread by direct contact with lesions or withnasal carriers. The incubation period is 1-3 days. Dried streptococci inthe air are not infectious to intact skin. Scratching may spread thelesions. Good hygiene practices can help prevent impetigo fromspreading.

Subtypes of impetigo contagiosa are bullous impetigo and eethyma.Bullous impetigo primarily affects infants and children younger than 2years. It causes painless, fluid-filled blisters—usually on the trunk,arms and legs. The skin around the blister is usually red and itchy butnot sore. The blisters, which break and scab over with a yellow-coloredcrust, may be large or small, and may last longer than sores from othertypes of impetigo. Eethyma is a more serious form of impetigo in whichthe infection penetrates deeper into the skin's second layer, thedermis. Signs and symptoms include:

-   -   Painful fluid- or pus-filled sores that turn into deep ulcers,        usually on the legs and feet    -   A hard, thick, gray-yellow crust covering the sores    -   Swollen lymph glands in the affected area    -   Little holes the size of pinheads to the size of pennies appear        after crust recedes    -   Scars that remain after the ulcers heal

For the treatment of impetigo contagiosa and its suptypes topical ororal antibiotics are usually prescribed. Mild cases can be treated withbactericidal ointment, such as fusidic acid, mupirocin, chloramphenicol,clioquinol or neosporin. More severe cases require oral antibiotics,such as dicloxacillin, flucloxacillin or erythromycin. Alternativelyamoxicillin combined with clavulanate potassium, cephalosporins (1stgeneration) and many others may also be used as an antibiotic treatment.The mentioned medicaments may be used in the form of any ofpharmaceutically acceptable salts, optical isomers, diastereomers,enantiomers, hydrates, and pharmaceutically acceptable salts thereof.

There are various disadvantages associated with the available treatmentsfor inflammatory skin diseases.

Retinoids are an available treatment options for acne. Clinicalimprovement following treatment with Retinoids typically requiresseveral weeks, and Retinoids are known to possess teratogenicproperties. Retinoids may also be irritants. Onset of action is quiterapid with BPO and resistance to P. Acnes has not been reported;however, BPO is a bleaching agent and, therefore, whitening of clothingand bedding may occur.

Furthermore, BPO is a potential irritant and may act as a mutagen. Thenumber of topical antibiotics currently used has led to high percentageof resistance. Thus, a need exists for improved treatments for acne andother inflammatory skin diseases.

1-Amino-alkylcyclohexane derivatives such as neramexane (also known as1-amino-1,3,3,5,5-pentamethylcyclohexane) have been found to be usefulin the therapy of various diseases especially in certain neurologicaldiseases, including Alzheimer's disease and neuropathic pain.1-Amino-alkylcyclohexane derivatives such as neramexane are disclosed indetail in U.S. Pat. Nos. 6,034,134 and 6,071,966, the subject matter ofwhich patents is hereby incorporated by reference.

Surprisingly, it has now been found that 1-amino-alkylcyclohexanederivatives such as neramexane are also suitable for treatinginflammatory skin diseases.

The beneficial impact of 1-amino-alkylcyclohexane derivatives such asneramexane on sebocytes also contributes to the effective treatment ofinflammatory skin diseases including acne, rosacea, eczema, atopicdermatitis, psoriasis and oily skin. The impact on proliferation and/ordifferentiation of sebocytes and thus the ability to reduce lipidproduction allows for regulation of sebum secretion. In addition tooverall sebum regulation, the composition of sebum may also beinfluenced, leading to normalization of the pathophysiological phenotypeof the diseased hair-follicle.

Patients with inflammatory skin diseases often exhibit a disturbedcutaneous barrier function. 1-Amino-alkylcyclohexane derivatives such asneramexane may improve the cutaneous barrier function and block thedelay of barrier recovery which results in a positive effect onhomeostasis of the skin.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating inflammatory skindiseases such as acne, rosacea, eczema, atopic dermatitis, psoriasis andoily skin in a subject in need thereof, comprising administering to theindividual an effective amount of a 1-amino-alkylcyclohexane derivative(e.g., neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate).

The present invention also relates to a method of treating aninflammatory skin disease such as impetigo contagiosa.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered in a range from about 5 mg to about150 mg/day or neramexane mesylate is administered in a range from about5 mg to about 100 mg/day, or neramexane mesylate is administered in arange from about 5 mg to about 75 mg/day, or wherein neramexane mesylateis administered at about 50 mg/day or wherein neramexane mesylate isadministered at about 75 mg/day for example in an oral formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered once a day, twice a day (b.i.d.), or three times a day.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered in an immediate release formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered in a modified release formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered in a topical formulation such as a topical rinse-off orleave-on formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered between 0.1 and 99% by weight of the formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered in an oral formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered systemically.

A further aspect of the invention relates to a method of treatinginflammatory skin diseases in a subject in need thereof, comprisingadministering to the individual an effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and an additional pharmaceutical agent (e.g., antimicrobial agents,antibiotics, retinoids or steroids) which has been shown to be effectivein treating or preventing inflammatory skin diseases.

A further aspect of the invention relates to a method of treating acnein a subject in need thereof, comprising administering to the individualan effective amount of a 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and an additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) which has beenshown to be effective in treating or preventing inflammatory skindiseases.

A further aspect of the invention relates to a method of treating acnein a subject in need thereof, comprising administering to the individualan effective amount of a 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and an additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids, steroids, or othernon-specific agents) which has been shown to be effective in treating orpreventing acne.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and the additional pharmaceutical agent (e.g., antimicrobial agents,antibiotics, retinoids or steroids) are administered conjointly.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and the additional pharmaceutical agent (e.g., antimicrobial agents,antibiotics, retinoids or steroids) are administered in a singleformulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and the additional pharmaceutical agent (e.g., antimicrobial agents,antibiotics, retinoids or steroids) are administered in a topicalformulation such as a topical rinse-off or leave-on formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and the additional pharmaceutical agent (e.g., antimicrobial agents,antibiotics, retinoids or steroids) are administered systemically.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and the additional pharmaceutical agent (e.g., antimicrobial agents,antibiotics, retinoids or steroids) are administered in an oralformulation.

A further aspect of the invention relates to a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) for the treatment of inflammatoryskin diseases such as acne, rosacea eczema, atopic dermatitis,psoriasis, and oily skin.

A further aspect of the invention relates to a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) for the treatment of a inflammatoryskin disease such as impetigo contagiosa.

A further aspect of the invention relates to the use of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)for the manufacture of a medicament for treatment of inflammatory skindiseases.

A further aspect of the invention relates to the above-definedderivative or use wherein neramexane mesylate is administered in a rangefrom about 5 mg to about 150 mg/day or neramexane mesylate isadministered in a range from about 5 mg to about 100 mg/day, orneramexane mesylate is administered in a range from about 5 mg to about75 mg/day, or wherein neramexane mesylate is administered at about 50mg/day or wherein neramexane mesylate is administered at about 75 mg/dayfor example in an oral formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered once a day, twice a day (b.i.d.),or three times a day.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered in an immediate release formulationor a modified release formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered in a topical formulation such as atopical rinse-off or leave-on formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered between 0.1 and 99% by weight ofthe formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered in an oral formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered systemically.

A further aspect of the invention relates to the above-definedderivative or use wherein at least one additional pharmaceutical agent(e.g., antimicrobial agents, antibiotics, retinoids or steroids) whichhas been shown to be effective in treating or preventing inflammatoryskin diseases is administered.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) areadministered conjointly.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) areadministered in a single formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) areadministered in a topical formulation such as a topical rinse-off orleave-on formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) areadministered in an oral formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) areadministered systemically.

A further aspect of the invention relates to a pharmaceuticalcomposition for the treatment of inflammatory skin diseases comprising atherapeutically effective amount of a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate), and, optionally, at least onepharmaceutically acceptable carrier or excipient.

A further aspect of the invention relates to a pharmaceuticalcomposition for the treatment of inflammatory skin diseases comprising atherapeutically effective amount of a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) in an immediate or modified releaseformulation.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) ina topical formulation.

A further aspect of the invention relates to a pharmaceuticalcomposition for the treatment of inflammatory skin diseases comprising atherapeutically effective amount of a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) in a topical formulation.

A further aspect of the invention relates to a pharmaceuticalcomposition for the treatment of inflammatory skin diseases comprising atherapeutically effective amount of a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) in an oral formulation.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) incombination with at least one additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) which has beenshown to be effective in treating inflammatory skin diseases and,optionally, at least one pharmaceutically acceptable carrier orexcipient.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) incombination with at least one additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) which has beenshown to be effective in treating or preventing inflammatory skindiseases and, optionally, at least one pharmaceutically acceptablecarrier or excipient.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) incombination with at least one additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids, steroids, or othernon-specific agents) which has been shown to be effective in treating orpreventing acne and, optionally, at least one pharmaceuticallyacceptable carrier or excipient.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) incombination with at least one additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) which has beenshown to be effective in treating inflammatory skin diseases and,optionally, at least one pharmaceutically acceptable carrier orexcipient in the form of a topical or oral formulation.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) incombination with at least one additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) which has beenshown to be effective in treating or preventing inflammatory skindiseases and, optionally, at least one pharmaceutically acceptablecarrier or excipient in the form of a topical or oral formulation.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) incombination with at least one additional pharmaceutical agent (e.g.,antimicrobial agents, antibiotics, retinoids or steroids) which has beenshown to be effective in treating or preventing acne and, optionally, atleast one pharmaceutically acceptable carrier or excipient in the formof a topical or oral formulation.

A further aspect of the invention relates to a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) for reducing secretion of sebumand/or regulating composition of sebum.

A further aspect of the invention relates to the use of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)for the manufacture of a medicament for reducing secretion of sebumand/or regulating composition of sebum.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered in a topical formulation such as atopical rinse-off or leave-on formulation.

A further aspect of the invention relates to a method of reducingsecretion of sebum and/or regulating composition of sebum in a subjectin need thereof, comprising administering to the indivival an effectiveamount of a 1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate).

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered in a topical formulation such as a topical rinse-off orleave-on formulation.

A further aspect of the invention relates to a method of treating orpreventing inflammatory skin diseases in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative selected from neramexane andpharmaceutically acceptable salts thereof.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative is neramexane mesylate.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered in a range from about 5 mg to about150 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered in a range from about 5 mg to about100 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered in a range from about 5 mg to about75 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered at about 50 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered at about 75 mg/day.

A further aspect of the invention relates to a method of treating orpreventing inflammatory skin diseases in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative selected from neramexane andpharmaceutically acceptable salts thereof, wherein the1-amino-alkylcyclohexane derivative is administered once a day, twice aday (b.i.d.), or three times a day.

A further aspect of the invention relates to a method of treating orpreventing inflammatory skin diseases in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative selected from neramexane andpharmaceutically acceptable salts thereof, wherein the1-amino-alkylcyclohexane derivative is administered in a topicalformulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative is administered between 0.1 and 99%by weight of the formulation.

A further aspect of the invention relates to a method of treating orpreventing inflammatory skin diseases in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative selected from neramexane andpharmaceutically acceptable salts thereof, wherein the1-amino-alkylcyclohexane derivative is administered in an oralformulation.

A further aspect of the invention relates to a method of treating orpreventing an inflammatory skin disease selected from acne, rosacea,eczema, atopic dermatitis, and oily skin in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative selected from neramexane andpharmaceutically acceptable salts thereof.

A further aspect of the invention relates to a method of treating orpreventing acne in a subject in need thereof, comprising administeringan effective amount of a 1-amino-alkylcyclohexane derivative selectedfrom neramexane and pharmaceutically acceptable salts thereof.

A further aspect of the invention relates to a method of treating orpreventing atopic dermatitis in a subject in need thereof, comprisingadministering an effective amount of a 1-amino-alkylcyclohexanederivative selected from neramexane and pharmaceutically acceptablesalts thereof.

A further aspect of the invention relates to a method of treating orpreventing impetigo contagiosa in a subject in need thereof, comprisingadministering an effective amount of a 1-amino-alkylcyclohexanederivative selected from neramexane and pharmaceutically acceptablesalts thereof.

A further aspect of the invention relates to a method of treating orpreventing inflammatory skin diseases, wherein the inflammatory skindisease is not psoriasis, in a subject in need thereof, comprisingadministering an effective amount of a 1-amino-alkylcyclohexanederivative selected from neramexane and pharmaceutically acceptablesalts thereof.

A further aspect of the invention relates to a method of treating orpreventing an inflammatory skin disease selected from acne, rosacea,eczema, atopic dermatitis, psoriasis, and oily skin in a subject in needthereof, comprising administering an effective amount of a1-amino-alkylcyclohexane derivative selected from neramexane andpharmaceutically acceptable salts thereof, wherein the1-amino-alkylcyclohexane derivative is administered in a topicalformulation.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative selected from neramexane andpharmaceutically acceptable salts thereof in combination with anadditional pharmaceutical agent which has been shown to be effective forthe treatment or the prevention of inflammatory skin diseases and,optionally, at least one pharmaceutically acceptable carrier orexcipient.

A further aspect of the invention relates to such a pharmaceuticalcomposition wherein the composition is in the form of a topicalformulation.

A further aspect of the invention relates to such a pharmaceuticalcomposition wherein the composition is in the form of an oralformulation.

A further aspect of the invention relates to such a pharmaceuticalcomposition wherein the 1-amino-alkylcyclohexane derivative isneramexane mesylate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 show the effects of neramexane in a contact hypersensitivitymouse model.

FIGS. 4-5 show the effects of neramexane in a dermatitis mouse model.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term inflammatory skin diseases includes acne,eczema, atopic dermatitis, rosacea, psoriasis and oily skin.

As used herein, the term inflammatory skin diseases also includesimpetigo contagiosa.

As used herein, the term impetigo contagiosa includes bullous impetigoand eethyma.

As used herein, the term acne includes acne vulgaris, persistent acne,and clinical acne.

As used herein, the term rosacea includes persistent edema of rosacea,rosacea conglobata, rosacea fulminans, ophthalmic rosacea, lupoid orgranulomatous rosacea, steroid rosacea, gram-negative rosacea, halogenrosacea, phymas in rosacea, erythematotelangiectatic rosacea,papulopustular rosacea, phymatous rosacea and ocular rosacea.

As used herein, the term eczema includes atopic eczema, irritant contactdermatitis, allergic contact dermatitis, occupational dermatitis,xerotic eczema, seborrhoeic dermatitis, syshidrosis, discoid eczema,venous eczema, dermatitis herpetiformis, neurodermatitis, andautoeczematization.

As used herein, the term psoriasis includes psoriasis vulgaris, plaquepsoriasis, flexural psoriasis, inverse psoriasis, guttate psoriasis,pustular psoriasis, nail psoriasis, erythrodermic psoriasis andpsoriatic arthritis.

As used herein, the term antimicrobial agents include topicalantimicrobial agents such as BPO, triclosan, chlorhexidine, salicylicacid, sulphur, resorcinol, and optical isomers, diastereomers,enantiomers, hydrates, their pharmaceutically acceptable salts, andmixtures thereof.

As used herein, the term antibiotics include topical antibiotics andoral antibiotics.

As used herein, the term topical antibiotics include erythromycin,clindamycin, tetracycline, metronidazole, and optical isomers,diastereomers, enantiomers, hydrates, their pharmaceutically acceptablesalts, and mixtures thereof.

As used herein, the term oral antibiotics include erythromycin,tetracycline, oxytetracycline, doxycycline, minocycline, lymecycline,trimethoprim, and optical isomers, diastereomers, enantiomers, hydrates,their pharmaceutically acceptable salts, and mixtures thereof.

As used herein, the term retinoids include topical retinoids and oralretinoids such as isotretinoin and optical isomers, diastereomers,enantiomers, hydrates, and its pharmaceutically acceptable salts.

As used herein, the term topical retinoids include retinol, tretinoin,isotretinoin, motretinide, adapalene, tazarotene, and optical isomers,diastereomers, enantiomers, hydrates, their pharmaceutically acceptablesalts, and mixtures thereof.

As used herein, the term steroids include spironolactone, drospirenone,cyproterone, cyproterone acetate, and optical isomers, diastereomers,enantiomers, hydrates, their pharmaceutically acceptable salts, andmixtures thereof.

As used herein, the term “subject” encompasses mammals including animalsand humans.

The term 1-amino-alkylcyclohexane derivative is used herein to describea 1-amino-alkylcyclohexane or a compound derived from1-amino-alkylcyclohexane, e.g., pharmaceutically acceptable salts of1-amino-alkylcyclohexanes.

The 1-amino-alkylcyclohexane derivatives of the present invention may berepresented by the general formula (I):

wherein R* is —(CH₂)_(n)—(CR⁸R⁷)_(m)—NR⁸R⁹wherein n+m=0, 1, or 2wherein R¹ through R⁷ are independently selected from the groupconsisting of hydrogen and C₁₋₆alkyl, wherein R⁸ and R⁹ areindependently selected from the group consisting of hydrogen andC₁₋₆alkyl or together represent lower-alkylene —(CH₂)_(x)— wherein x is2 to 5, inclusive, and optical isomers, enantiomers, hydrates, andpharmaceutically-acceptable salts thereof.

Non-limiting examples of the 1-amino-alkylcyclohexanes used according tothe present invention include:

-   1-amino-1,3,5-trimethylcyclohexane,-   1-amino-[(trans),3(trans),5-trimethylcyclohexane,-   1-amino-1(cis),3(cis),5-trimethylcyclohexane,-   1-amino-1,3,3,5-tetramethylcyclohexane,-   1-amino-1,3,3,5,5-pentamethylcyclohexane (neramexane),-   1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,-   1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,-   1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane,-   1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane,-   1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane,-   1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane,-   1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,-   1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,-   N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   N-ethyl-1-amino-1,3,3,5,5-pentamethyl-cyclohexane,-   N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine,-   3,3,5,5-tetramethylcyclohexylmethylamine,-   1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,-   1 amino-1,3,3,5(trans)-tetramethylcyclohexane (axial amino group),-   3-propyl-1,3,5,5-tetramethylcyclohexylamine semihydrate,-   1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,-   1-amino-1,3,5-trimethylcyclohexane,-   1-amino-1,3-dimethyl-3-propylcyclohexane,-   1-amino-1,3(trans),5(trans)-trimethyl-3(cis)-propylcyclohexane,-   1-amino-1,3-dimethyl-3-ethylcyclohexane,-   1-amino-1,3,3-trimethylcyclohexane,-   cis-3-ethyl-1(trans)-3(trans)-5-trimethylcyclohexamine,-   1-amino-1,3(trans)-dimethylcyclohexane,-   1,3,3-trimethyl-5,5-dipropylcyclohexylamine,-   1-amino-1-methyl-3(trans)-propylcyclohexane,-   1-methyl-3(cis)-propylcyclohexylamine,-   1-amino-1-methyl-3(trans)-ethylcyclohexane,-   1-amino-1,3,3-trimethyl-5(cis)-ethylcyclohexane,-   1-amino-1,3,3-trimethyl-5(trans)-ethylcyclohexane,-   cis-3-propyl-1,5,5-trimethylcyclohexylamine,-   trans-3-propyl-1,5,5-trimethylcyclohexylamine,-   N-ethyl-1,3,3,5,5-pentamethylcyclohexylamine,-   N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   1-amino-1-methylcyclohexane,-   N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   2-(3,3,5,5-tetramethylcyclohexyl)ethylamine,-   2-methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine,-   2-(1,3,3,5,5-pentamethylcyclohexyl-1)-ethylamine semihydrate,-   N-(1,3,3,5,5-pentamethylcyclohexyl)-pyrrolidine,-   1-amino-1,3(trans),5(trans)-trimethylcyclohexane,-   1-amino-1,3(cis),5(cis)-trimethylcyclohexane,-   1-amino-(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexane,-   1-amino-(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexane,-   1-amino-1,5,5-trimethyl-3(cis)-isopropyl-cyclohexane,-   1-amino-1,5,5-trimethyl-3(trans)-isopropyl-cyclohexane,-   1-amino-1-methyl-3(cis)-ethyl-cyclohexane,-   1-amino-1-methyl-3(cis)-methyl-cyclohexane,-   1-amino-5,5-diethyl-1,3,3-trimethyl-cyclohexane,-   1-amino-1,3,3,5,5-pentamethylcyclohexane,-   1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,-   1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,-   N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   N-(1,3,5-trimethylcyclohexyl)pyrrolidine or piperidine,-   N-[1,3(trans),5(trans)-trimethylcyclohexyl]pyrrolidine or    piperidine,-   N-[1,3(cis),5(cis)-trimethylcyclohexyl]pyrrolidine or piperidine,-   N-(1,3,3,5-tetramethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,5,5-trimethyl-3,3-diethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,3-trimethyl-cis-5-ethylcyclohexyl)pyrrolidine or piperidine,-   N-[(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexyl]pyrrolidine or    piperidine,-   N-(1,3,3-trimethyl-trans-5-ethylcyclohexyl)pyrrolidine or    piperidine,-   N-[(1R,5S)trans-5-ethyl,3,3-trimethylcyclohexyl]pyrrolidine or    piperidine,-   N-(1-ethyl-3,3,5,5-tetramethylyclohexyl)pyrrolidine or piperidine,-   N-(1-propyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine,    and optical isomers, diastereomers, enantiomers, hydrates, their    pharmaceutically acceptable salts, and mixtures thereof.

1-Amino-alkylcyclohexane derivatives (e.g., neramexane,1-amino-1,3,3,5,5-pentamethylcyclohexane) are disclosed in U.S. Pat.Nos. 6,034,134 and 6,071,966. 1-Amino-alkylcyclohexane derivatives(e.g., neramexane) may be used according to the invention in the form ofany of pharmaceutically acceptable salts, solvates, isomers, conjugates,and prodrugs, any references to 1-amino-alkylcyclohexane derivatives(e.g., neramexane) in this description should be understood as alsoreferring to such salts, solvates, isomers, conjugates, and prodrugs.

Pharmaceutically acceptable salts include, but are not limited to, acidaddition salts, such as those made with hydrochloric, methylsulfonic,hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric,acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic,fumaric, tartaric, citric, benzoic, carbonic, cinnamic, mandelic,methanesulfonic, ethanesulfonic, hydroxyethanesulfonic,benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic,p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid. All ofthese salts (or other similar salts) may be prepared by conventionalmeans. The nature of the salt is not critical, provided that it isnon-toxic and does not substantially interfere with the desiredpharmacological activity.

The term “analog” or “derivative” is used herein in the conventionalpharmaceutical sense, to refer to a molecule that structurally resemblesa reference molecule (such as neramexane), but has been modified in atargeted and controlled manner to replace one or more specificsubstituents of the reference molecule with an alternate substituent,thereby generating a molecule which is structurally similar to thereference molecule. Synthesis and screening of analogs (e.g., usingstructural and/or biochemical analysis), to identify slightly modifiedversions of a known compound which may have improved or biased traits(such as higher potency and/or selectivity at a specific targetedreceptor type, greater ability to penetrate mammalian barriers, such ascell membranes, fewer side effects, etc.) is a drug design approach thatis well known in pharmaceutical chemistry.

The term “treat” is used herein to mean to relieve or alleviate at leastone symptom of a disease in a subject. Within the meaning of the presentinvention, the term “treat” also denotes to arrest, delay the onset(i.e., the period prior to clinical manifestation of a disease) and/orreduce the risk of developing or worsening a disease.

The term “therapeutically effective” applied to dose or amount refers tothat quantity of a compound or pharmaceutical composition that issufficient to result in a desired activity upon administration to amammal in need thereof.

The phrase “pharmaceutically acceptable”, as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to amammal (e.g., human). The term “pharmaceutically acceptable” may alsomean approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in mammals, and more particularly inhumans.

The term “carrier” applied to pharmaceutical compositions of theinvention refers to a diluent, excipient, or vehicle with which anactive compound (e.g., neramexane) is administered. Such pharmaceuticalcarriers can be liquids, such as water, saline solutions, aqueousdextrose solutions, aqueous glycerol solutions, and oils, includingthose of petroleum, animal, vegetable or synthetic origin, such aspeanut oil, soybean oil, mineral oil, sesame oil and the like. Suitablepharmaceutical carriers are described e.g. in “Remington'sPharmaceutical Sciences” by A. R. Gennaro, 20^(th) Edition.

The term “about” or “approximately” usually means within 20%,alternatively within 10%, including within 5% of a given value or range.Alternatively, especially in biological systems, the term “about” meanswithin about a log (i.e., an order of magnitude), including within afactor of two of a given value.

Pharmaceutical Formulations and Administration

In conjunction with the methods of the present invention, also providedare pharmaceutical compositions comprising a therapeutically effectiveamount of a 1-amino-alkylcyclohexane derivative (e.g., neramexane). Thecompositions of the invention may further comprise a carrier orexcipient (all pharmaceutically acceptable). The compositions may beformulated for once-a-day administration, twice-a-day administration, orthree times a day administration.

The active ingredient (e.g., neramexane, such as neramexane mesylate) orthe composition of the present invention may be used for the treatmentof at least one of the mentioned disorders, wherein the treatment isadapted to or appropriately prepared for a specific administration asdisclosed herein (e.g., to once-a-day, twice-a-day, or three times a dayadministration). For this purpose the package leaflet and/or the patientinformation contains corresponding information.

The active ingredient (e.g., neramexane, such as neramexane mesylate) orthe composition of the present invention may be used for the manufactureof a medicament for the treatment of at least one of the mentioneddisorders, wherein the medicament is adapted to or appropriatelyprepared for a specific administration as disclosed herein (e.g., toonce-a-day, twice-a-day, or three times a day administration). For thispurpose the package leaflet and/or the patient information containscorresponding information.

According to the present invention, the dosage form of the1-amino-alkylcyclohexane derivative (e.g., neramexane) may be a solid,semisolid, or liquid formulation according to the following.

The 1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be administered orally, topically, parenterally, ormucosally (e.g., buccally, by inhalation, or rectally) in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers. In another embodiment for administration topediatric subjects, the 1-amino-alkylcyclohexane derivative may beformulated as a flavored liquid (e.g., peppermint flavor). The1-amino-alkylcyclohexane derivatives of the present invention may beadministered orally in the form of a capsule, a tablet, or the like, oras a liquid formulation or topically as a semi-solid such as anointment, cream, gel, hydrogel (see Remington's Pharmaceutical Sciences,20^(th) Edition, by A. R. Gennaro).

For oral administration in the form of a tablet or capsule, the1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be combined with non-toxic, pharmaceutically acceptableexcipients such as binding agents (e.g., pregelatinized maize starch,polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.,lactose, sucrose, glucose, mannitol, sorbitol and other reducing andnon-reducing sugars, microcrystalline cellulose, calcium sulfate, orcalcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc,or silica, steric acid, sodium stearyl fumarate, glyceryl behenate,calcium stearate, and the like); disintegrants (e.g., potato starch orsodium starch glycolate); or wetting agents (e.g., sodium laurylsulphate), coloring and flavoring agents, gelatin, sweeteners, naturaland synthetic gums (such as acacia, tragacanth or alginates), buffersalts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like.

The tablets may be coated with a concentrated sugar solution which maycontain e.g., gum arabic, gelatine, talcum, titanium dioxide, and thelike. Alternatively, the tablets can be coated with a polymer thatdissolves in a readily volatile organic solvent or mixture of organicsolvents. In specific embodiments, neramexane is formulated inimmediate-release (IR) or modified-release (MR) dosage forms. Immediaterelease solid dosage forms permit the release of most or all of theactive ingredient over a short period of time, such as 60 minutes orless, and make rapid absorption of the drug possible (immediate releaseformulations of 1-amino-alkylcyclohexanes such as neramexane aredisclosed in US Published Application Nos. 2006/0002999 and2006/0198884, the subject matter of which is hereby incorporated byreference). Modified release solid oral dosage forms permit thesustained release of the active ingredient over an extended period oftime in an effort to maintain therapeutically effective plasma levelsover similarly extended time intervals and/or to modify otherpharmacokinetic properties of the active ingredient (modified releaseformulations of neramexane are disclosed in US Published Application No.2007/0141148, the subject matter of which is hereby incorporated byreference).

For the formulation of soft gelatin capsules, the1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be admixed with e.g., a vegetable oil or poly-ethyleneglycol. Hard gelatin capsules may contain granules of the activesubstances using either the above mentioned excipients for tablets e.g.,lactose, saccharose, sorbitol, mannitol, starches (e.g., potato starch,corn starch or amylopectin), cellulose derivatives or gelatine. Alsoliquids or semisolids of the drug can be filled into hard gelatinecapsules.

The 1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) can also be introduced in microspheres or microcapsules,e.g., fabricated from polyglycolic acid/lactic acid (PGLA) (see, e.g.,U.S. Pat. Nos. 5,814,344; 5,100,669 and 4,849,222; PCT Publications No.WO 95/11010 and WO 93/07861). Biocompatible polymers may be used inachieving controlled release of a drug, include for example, polylacticacid, polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters,polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked oramphipathic block copolymers of hydrogels.

Formulation of the 1-amino-alkylcyclohexane derivatives of the presentinvention in a semi-solid or liquid form may also be used. The1-amino-alkylcyclohexane derivative (e.g., neramexane) may constitutebetween 0.1 and 99% by weight of the formulation, more specificallybetween 0.5 and 20% by weight for formulations intended for injectionand between 0.2 and 50% by weight for formulations suitable for oraladministration.

Formulations of the 1-amino-alkylcyclohexane derivatives of the presentinvention in a semi-solid or liquid form suitable for topicaladministration may also be used.

Alternatively, formulations of the 1-amino-alkylcyclohexane derivativesof the present invention in a dry (solid) suitable for topicaladministration may be used.

Such formulations include gels, creams, ointments, hydrogels, pastes,emulsions, sprays, solutions, lotions, etc.

Such formulations also include powders, oleogels, suspensions, oil inwater emulsions, water in oil emulsions, multiple emulsions, micro- andnanoemulsions, self emulsifying systems, aqueous and non aqueoussolutions, patches, or transdermal systems. Combinations of theabove-mentioned formulations may also be used.

The 1-amino-alkylcyclohexane derivative (e.g., neramexane) mayconstitute between 0.1 and 99% by weight of the formulation, morespecifically between 0,5% and 50% by weight of the formulation orbetween 1% and 25% by weight of the formulation or between 2% and 20% byweight of the formulation.

In one embodiment of the invention, the 1-amino-alkylcyclohexanederivative (e.g., neramexane) is administered in a modified releaseformulation. Modified release dosage forms provide a means for improvingpatient compliance and for ensuring effective and safe therapy byreducing the incidence of adverse drug reactions. Compared to immediaterelease dosage forms, modified release dosage forms can be used toprolong pharmacologic action after administration, and to reducevariability in the plasma concentration of a drug throughout the dosageinterval, thereby eliminating or reducing sharp peaks.

A modified release dosage form may comprise a core either coated with orcontaining a drug. The core is then coated with a release modifyingpolymer within which the drug is dispersed. The release modifyingpolymer disintegrates gradually, releasing the drug over time. Thus, theouter-most layer of the composition effectively slows down and therebyregulates the diffusion of the drug across the coating layer when thecomposition is exposed to an aqueous environment, i.e. thegastrointestinal tract. The net rate of diffusion of the drug is mainlydependent on the ability of the gastric fluid to penetrate the coatinglayer or matrix and on the solubility of the drug itself.

In another embodiment of the invention, the 1-amino-alkylcyclohexanederivative (e.g., neramexane) is formulated in an oral, liquidformulation. Liquid preparations for oral administration can take theform of, for example, solutions, syrups, emulsions or suspensions, orthey can be presented as a dry product for reconstitution with water orother suitable vehicle before use. Preparations for oral administrationcan be suitably formulated to give controlled or postponed release ofthe active compound. Oral liquid formulations of1-amino-alkylcyclohexanes, such as neramexane, are described in PCTInternational Application No. PCT/US2004/037026, the subject matter ofwhich is hereby incorporated by reference.

For oral administration in liquid form, 1-amino-alkylcyclohexanederivatives of the present invention (e.g., neramexane) may be combinedwith non-toxic, pharmaceutically acceptable inert carriers (e.g.,ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oilyesters, ethyl alcohol or fractionated vegetable oils), preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and thelike. Stabilizing agents such as antioxidants (e.g. BHA, BHT, propylgallate, sodium ascorbate, citric acid) can also be added to stabilizethe dosage forms. For example, solutions may contain from about 0.2% toabout 20% by weight of neramexane, with the balance being sugar andmixture of ethanol, water, glycerol and propylene glycol. Optionally,such liquid formulations may contain coloring agents, flavoring agents,sweetening agents and thickening agents, such ascarboxymethyl-cellulose, or other excipients.

In another embodiment, a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane) is administeredin an oral solution containing a preservative, a sweetener, asolubilizer, and a solvent. The oral solution may include one or morebuffers, flavorings, or additional excipients. In a further embodiment,a peppermint or other flavoring is added to the neramexane derivativeoral liquid formulation.

For administration by inhalation, 1-amino-alkylcyclohexane derivatives(e.g., neramexane) of the present invention may be convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In thecase of a pressurized aerosol, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, e.g., gelatin for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Solutions for parenteral applications by injection may be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substances, for example in a concentration of from about 0.5%to about 10% by weight. These solutions may also contain stabilizingagents and/or buffering agents and may conveniently be provided invarious dosage unit ampoules.

The formulations of the invention may be delivered parenterally, i.e.,by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous(s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.),or intradermal (i.d.) administration, by direct injection, via, forexample, bolus injection or continuous infusion. Formulations forinjection can be presented in unit dosage form, e.g., in ampoules or inmulti-dose containers, with an added preservative. Alternatively, theactive ingredient may be in powder form for reconstitution with asuitable vehicle, e.g., sterile pyrogen-free water, before use.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers containing a 1-amino-alkylcyclohexane derivative(e.g., neramexane) and, optionally, more of the ingredients of theformulation. In a specific embodiment, neramexane is provided as an oralsolution (2 mg/ml) for administration with the use of a 2 teaspooncapacity syringe (dosage KORC®). Each oral syringe has hatch marks formeasurement, with lines on the right side of the syringe (tip down)representing tsp units, and those on the left representing ml units.

The optimal therapeutically effective amount may be determinedexperimentally, taking into consideration the exact mode ofadministration, from in which the drug is administered, the indicationtoward which the administration is directed, the subject involved (e.g.,body weight, health, age, sex, etc.), and the preference and experienceof the physician or veterinarian in charge.

Dosage units for rectal application may be solutions or suspensions ormay be prepared in the form of suppositories or retention enemascomprising neramexane in a mixture with a neutral fatty base, or gelatinrectal capsules comprising the active substances in admixture withvegetable oil or paraffin oil.

Toxicity and therapeutic efficacy of the compositions of the inventionmay be determined by standard pharmaceutical procedures in experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between therapeutic and toxic effects isthe therapeutic index and it may be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferred.

Suitable daily doses of the active compounds of the invention intherapeutic treatment of humans are about 0.01-10 mg/kg bodyweight onperoral administration and 0.001-10 mg/kg bodyweight on parenteraladministration. For example, for adults, suitable daily doses ofneramexane (e.g. neramexane mesylate) are within the range from about 5mg to about 150 mg per day, such as from about 5 mg to about 120 mg,from about 5 mg to about 100 mg, or from about 5 mg to about 75 mg, orfrom about 5 mg to about 50 mg, such as 25 mg or 37.5 mg or 50 mg, perday. For example the daily dose may be body weight-adjusted such as 50mg/day up to 90 kg body weight or 75 mg/day for patients with a bodyweight of 90 kg. An equimolar amount of another pharmaceuticallyacceptable salt, a solvate, an isomer, a conjugate, a prodrug or aderivative thereof, such as neramexane hydrochloride, is also suitable.For pediatric subjects aged 4-14, neramexane (e.g. neramexane mesylate)may be administered as an oral, liquid dosage form, at about 0.5 mg/day,up to a maximum dose of 10 mg/day.

The daily doses indicated herein may be administered, for example, asone or two dosing units once, twice or three times per day. Suitabledoses per dosage unit may therefore be the daily dose divided (forexample, equally) between the number of dosage units administered perday, and will thus typically be about equal to the daily dose or onehalf, one third, one quarter or one sixth thereof. Dosages per dosageunit may thus be calculated from each daily dosage indicated herein. Adaily dose of 5 mg, for example may be seen as providing a dose perdosage unit of, for example, about 5 mg, 2.5 mg, 1.67 mg, 1.25 mg and0.83 mg, depending upon the dosing regimen chosen. Correspondingly, adosage of 150 mg per day corresponds to dosages per dosing unit of, forexample, about 150 mg, 75 mg, 50 mg, 37.5 mg, and 25 mg forcorresponding dosing regimens.

Treatment duration may be short-term, e.g., several weeks (for example8-14 weeks), or long-term until the attending physician deems furtheradministration no longer is necessary.

The 1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be administered as a monotherapy, or in combination withanother agent prescribed for the treatment of inflammatory skindiseases.

The term “combination” applied to active ingredients is used herein todefine a single pharmaceutical composition (formulation) comprising twoactive agents (e.g., a pharmaceutical composition comprising a1-amino-alkylcyclohexane derivative, such as neramexane, and anotheragent prescribed for the treatment of inflammatory skin diseases) or twoseparate pharmaceutical compositions, each comprising an active agent(e.g. a pharmaceutical composition comprising a 1-amino-alkylcyclohexanederivative, such as neramexane, and another pharmaceutical compositioncomprising another agent prescribed for the treatment of inflammatoryskin diseases), to be administered conjointly.

Within the meaning of the present invention, the term “conjointadministration” is used to refer to administration of1-amino-alkylcyclohexane derivative, such as neramexane, and one or moreadditional active agents (e.g. another agent prescribed for thetreatment of inflammatory skin diseases such as antimicrobial agents,antibiotics, retinoids or steroids) simultaneously in one composition,or simultaneously in different compositions, or sequentially. For thesequential administration to be considered “conjoint”, however,1-amino-alkylcyclohexane derivative, such as neramexane, and the one ormore additional active agents must be administered separated by a timeinterval which still permits the resultant beneficial effect fortreating inflammatory skin diseases in a mammal.

Examples of Representative Formulations

With the aid of commonly used solvents, auxiliary agents and carriers,active ingredients may be processed into tablets, coated tablets,capsules, drip solutions, suppositories, injection and infusionpreparations, gels, creams, ointments, and the like and can betherapeutically applied by the oral, rectal, parenteral, topical, andadditional routes. Tablets suitable for oral administration may beprepared by conventional tabletting techniques.

The following example is given by way of illustration only and is not tobe construed as limiting.

Formulation Example 1 Neramexane Mesylate Immediate Release Tablets

The following tables provide the make-up of neramexane immediate releasetablets in 12.5, 25.0, 37.5, and 50.0 mg dosages, including activecomponents, coating agents, and other excipients.

TABLE 1 Neramexane mesylate, 12.5 mg film coated tablets ComponentAmount [mg] Function Neramexane mesylate 12.50 Active pharmaceuticalingredient Cellulose microcrystalline 103.25 Binder Croscarmellosesodium 6.25 Disintegrant Silicon dioxide, colloidal 1.25 Flow promoterTalc 1.25 Glident Magnesium stearate 0.50 Lubricant core weight 125.00Coating (HPMC), Opadry or 5.00 Coating Sepifilm Coat weight 5.00 coatedtablet total weight 130.00

TABLE 2 Neramexane mesylate, 25.0 mg film coated tablets ComponentAmount [mg] Function Neramexane mesylate 25.00 Active pharmaceuticalingredient Cellulose microcrystalline 206.50 Binder Croscarmellosesodium 12.5 Disintegrant Silicon dioxide, colloidal 2.50 Flow promoterTalc 2.50 Glident Magnesium stearate 1.00 Lubricant core weight 250.00Coating (HPMC), Opadry or 10.00 Coating Sepifilm Coat weight 10.00coated tablet total weight 260.00

TABLE 3 Neramexane mesylate, 37.5 mg film coated tablets ComponentAmount [mg] Function Neramexane mesylate 37.50 Active pharmaceuticalingredient Cellulose microcrystalline 309.75 Binder Croscarmellosesodium 18.75 Disintegrant Silicon dioxide, colloidal 3.75 Flow promoterTalc 3.75 Glident Magnesium stearate 1.50 Lubricant core weight 375.00Coating (HPMC), Opadry or 15.00 Coating Sepifilm Coat weight 15.00coated tablet total weight 390.00

TABLE 4 Neramexane mesylate, 50.0 mg film coated tablets ComponentAmount [mg] Function Neramexane mesylate 50.00 Active pharmaceuticalingredient Cellulose microcrystalline 413.00 Binder Croscarmellosesodium 25.00 Disintegrant Silicon dioxide, colloidal 5.00 Flow promoterTalc 5.00 Glident Magnesium stearate 2.00 Lubricant core weight 500.00Coating (HPMC), Opadry or 20.00 Coating Sepifilm Coat weight 20.00coated tablet total weight 520.00

The following tables provide the make-up of Neramexane topicalformulations.

Formulation Example 2

TABLE 5 “Unguentum emulsificans” Description Amount Alcohol cetylicus etstearylicus 30.0 g emulsificans Paraffinum subliquidum 35.0 g Vaselinumalbum 35.0 g

TABLE 6 “Unguentum emulsificans aquosum” containing 1% NeramexaneDescription Amount Neramexane mesylate 1.0 g Unguentum emulsificans 30.0g Aqua purificata 69.0 g

TABLE 7 “Unguentum emulsificans aquosum” containing 20% NeramexaneDescription Amount Neramexane mesylate 20.0 g Unguentum emulsificans30.0 g Aqua purificata 50.0 g

Formulation Example 3

TABLE 8 “Cremor nonionicus emulsificans aquosum” Description AmountAlcohol cetylicus et stearylicus 21.0 g emulsificans nonionicum2-Ethylhexylis lauras 10.0 g Glycerolum 85% 5.0 g Kalium sorbinicum 0.14g Acidum citricum, anhydricum 0.07 g Aqua purificata 63.79 g

TABLE 9 “Cremor nonionicus emulsificans aquosum” containing 1%Neramexane Description Amount Neramexane mesylate 1.0 g Cremornonionicus emulsificans 99.0 g aquosum

TABLE 10 “Cremor nonionicus emulsificans aquosum” containing 10%Neramexane Description Amount Neramexane mesylate 10.0 g Cremornonionicus emulsificans 90.0 g aquosum

Formulation Example 4

TABLE 11 “Macrogoli unguentum” Description Amount Macrogolum 300 50.0 gMacrogolum 1500 50.0 g

TABLE 12 “Macrogoli unguentum” containing 2% Neramexane DescriptionAmount Neramexane mesylate 2.0 g Macrogoli unguentum 98.0 g

TABLE 13 “Macrogoli unguentum” containing 15% Neramexane DescriptionAmount Neramexane mesylate 15.0 g Macrogoli unguentum 85.0 g

Formulation Example 5

TABLE 14 “Linimentum nonionicum aquosum” Description Amount Alcoholcetylicus et stearylicus 10.5 g emulsificans nonionicum 2-Ethylhexylislauras 5.0 g Glycerolum 85% 2.5 g Kalium sorbinicum 0.14 g Acidumcitricum, anhydricum 0.07 g Aqua purificata 81.79 g

TABLE 15 “Linimentum nonionicum aquosum” containing 3% NeramexaneDescription Amount Neramexane mesylate 3.0 g Linimentum nonionicumaquosum 97.0 g

TABLE 16 “Linimentum nonionicum aquosum” containing 12% NeramexaneDescription Amount Neramexane mesylate 12.0 g Linimentum nonionicumaquosum 88.0 g

TABLE 17 “Linimentum nonionicum aquosum” containing 25% NeramexaneDescription Amount Neramexane mesylate 25.0 g Linimentum nonionicumaquosum 75.0 g

EXAMPLES

The following examples illustrate the invention without limiting itsscope.

Example 1 Effects of Neramexane in a Contact Hypersensitivity MouseModel

The contact hypersensitivity model (CHS) induced by epicutaneousapplication of haptens serves as a model for a delayed typehypersensitivity reaction (Schwarz et al., 2004, The Journal ofImmunology, 172:1036-1043). Antigen-specific T lymphocytes are inducedwhich can be demonstrated by adoptive transfer experiments. Ear swellingresponse is only induced in mice which have been successfullysensitized, indicating that the response is an immune response and not atoxic reaction. Negative controls, i.e., mice which have not beensensitized, do not respond with ear swelling upon first application ofthe hapten on their ears. Since suppression of the sensitization bydrugs may indicate immunosuppressive activity of the respectivesubstance, the CHS model is utilized to screen drugs forimmunosuppressive properties.

Although the ear swelling response (challenge) also reflects an immuneresponse (T lymphocytes are the essential mediators), the ear swellingresponse is finally mediated via inflammatory cytokines which areinduced by the antigen-specific T lymphocytes. Thus, the challenge ofthis immune reaction can also be suppressed by antiinflammatory drugs.Thus, the CHS model is utilized to measure antiinflammatory propertiesand also allows for a differentiation between substances withimmunosuppressive and antiinflammatory properties.

Neramexane is tested for its efficacy in influencing immunologic and/orinflammatory reactions.

Materials and Methods Animals

For this study C57BL/6N male mice (6-8 weeks, approximately 20 g) areused.

The animals are allowed to acclimatise for 5 days before the start ofthe study. There is automatic control of light cycle, temperature andhumidity. Light cycles are 12 hours. Daily monitoring indicates thattemperature and humidity remain within the target ranges of 21° C.±1° C.and 50±5%, respectively. The animals are housed in polypropylene cages(Ebeco, type M-3) with mesh tops (up to 7 mice are housed per cage).Cages, bedding, and water bottles are changed at regular intervals, i.e.every 7 days. Standard Diet (vendor) is available to the animals adlibitum. The animals have access to domestic quality mains water adlibitum.

Drugs

Neramexane mesylate is diluted with NaCl solution and freshly preparedfor each injection, and dose levels are determined via a pharmacokineticpilot study. Based on the pilot study, a dose of 5 mg/kg 1 hour beforesensitization followed by a dose of 3.2 mg/kg injected 1 and 3 hoursafter sensitization is used.

Treatment

Upon arrival, all animals are randomly allocated to treatment groups,such that the treatment groups are evenly distributed throughout thecaging system.

The treatment groups and animal numbers are arranged as shown in Table18:

TABLE 18 Number of Treatment Dose Level Animals Group Group (mg · kg⁻¹ ·day⁻¹)* in Exp. 1, 2, 3 1 Positive Control 0 3, 5, 8 2 Negative Control0 2, 3, 5 3 Neramexane before 5 mg/kg 1 hr before 6, 7, 8 sensitizationsensitization, 3.2 mg/kg 1 hr and 3.2 mg/kg 3 hr after sensitization 4Neramexane before 5 mg/kg 1 hr before 6, 7, 8 challenge challenge, 3.2mg/kg 1 hr and 3.2 mg/kg 3 hr after challenge Dose refers to freebase/acid, the conversion factor from free base to salt form is 1.57.

The animals are injected intraperitoneally (i.p.) at a constant dosevolume of 200 μl ml dosing solution per kg of body weight, using a steeldosing cannula. The volume administered to each animal is determinedeach day by the weight of that animal at the time of administration.

Mice are sensitized by painting 50 μl of dinitrofluorobenzene (DNFB,Sigma Corp., St. Louis, Mo.) solution (0.5% in acetone:olive oil, 4:1)on the shaved back on day 0. On day 5, 20 μl of 0.3% DNFB is applied tothe left ear. Ear swelling is quantified with a spring-loaded micrometer24 hours after elicitation. Contact hypersensitivity (CHS) is determinedas the amount of swelling of the hapten-challenged ear compared to thethickness of the vehicle-treated ear and expressed in cm×10⁻³ (mean±SD).For positive control, animals are sensitized with 50 μl of 0.5% DNFBthrough the shaved skin. Challenge is performed 5 days later on the leftear (0.3% DNFB, 20 μl). Ear thickness is measured 24 hours later(cm×10⁻³). For negative control, mice are challenged with 0.3% DNFB, 20μl and ear thickness is measured 24 hours later (cm×10⁻³).

Evaluation of Data

Sensitization results are analyzed using one way ANOVA (excludingnegative control group) followed by Dunnett as post-hoc test. Theresults are shown in FIGS. 1-3

Results

Neramexane does not appear to have an impact on the induction of animmune response; however, administration of neramexane around challengesignificantly reduces ear swelling response. These results indicate thatneramexane may exert antiinflammatory but not immunosuppressiveproperties and that nermexane may be useful in treating inflammatoryskin diseases such as acne, rosacea, eczema, atopic dermatitis,psoriasis and oily skin.

Example 2 Effects of Neramexane in a dermatitis mouse model

In order to further test for antiinflammatory properties, an irritantdermatitis mouse model is used. Induction of an ear swelling response bycroton oil is a toxic reaction. This response is aconcentration-dependent phenomenon, independent of sensitizedlymphocytes.

Antiinflammatory substances have been shown to reduce the ear swellingresponse to a certain degree.

Neramexane is tested for its antiinflammatory properties.

Animals

For this study C57BL/6N male mice (6-8 weeks, approximately 20 g) areused.

The animals are allowed to acclimatise for 5 days before the start ofthe study. There is automatic control of light cycle, temperature andhumidity. Light cycles are 12 hours. Daily monitoring indicates thattemperature and humidity remain within the target ranges of 21° C.±1° C.and 50±5%, respectively. The animals are housed in polypropylene cages(Ebeco, type M-3) with mesh tops (up to 7 mice are housed per cage).Cages, bedding, and water bottles are changed at regular intervals, i.e.every 7 days. Standard Diet (vendor) is available to the animals adlibitum. The animals have access to domestic quality mains water adlibitum.

Drugs

Neramexane mesylate is diluted with NaCl solution and freshly preparedfor each injection, and dose levels are determined via a pharmacokineticpilot study. Based on the pilot study, a dose of 5 mg/kg 1 hour beforesensitization followed by a dose of 3.2 mg/kg injected 1 and 3 hoursafter sensitization is used.

Treatment

Upon arrival, all animals are randomly allocated to treatment groups,such that the treatment groups are evenly distributed throughout thecaging system.

The treatment groups and animal numbers are arranged as shown in Table19:

TABLE 19 Number of Treatment Dose Level Animals Group Group (mg · kg⁻¹ ·day⁻¹)* in Exp. 1, 2 1 Positive Control 0 4, 7 2 Negative Control 0 2, 53 Neramexane before 5 mg/kg 1 hr before 8, 8 irritation irritation, 3.2mg/kg 1 hr and 3.2 mg/kg 3 hr after irritation Dose refers to freebase/acid, the conversion factor from free base to salt form is 1.57.

The animals are injected intraperitoneally (i.p.) at a constant dosevolume of 200 μl ml dosing solution per kg of body weight, using a steeldosing cannula. The volume administered to each animal is determinedeach day by the weight of that animal at the time of administration.

The animals are injected intraperitoneally (i.p.) at a constant dosevolume of 200 μl ml dosing solution per kg of body weight, using a steeldosing cannula. The volume administered to each animal is determinedeach day by the weight of that animal at the time of administration.

20 μl of 1% croton oil in acetone is applied on the left ear. Earswelling is measured after 7 hours and 24 hours. Ear swelling isquantified with a springloaded micrometer. Irritant reaction isdetermined as the amount of swelling of the irritant-treated earcompared to the thickness of the vehicle (acetone)-treated ear andexpressed in cm×10⁻³. An additional group is treated with neramexane (asdescribed above) and croton oil.

Evaluation of Data

Sensitization results are analyzed using student test (comparisonbetween treatment and positive control). The results are shown in FIGS.4-5.

Results

Neramexane reduces the ear swelling response induced by croton oil tosome degree, indicating that neramexane may be useful in the treatmentof inflammatory skin diseases such as acne, rosacea, eczema, atopicdermatitis, psoriasis and oily skin.

Example 3 Antimicrobial properties of Neramexane againstPropionibacterium acnes

In order to determine the efficacy of Neramexane against a specificmicroorganism population (i.e., Propionibacterium acnes), a logreduction assay is performed.

The organisms are prepared by inoculating the fluid thioglycolate (FTM).The microorganism is then incubated at 35.2±2.5° C. for 24 hours. Themicrobial suspension is adjusted to approximately 107 to 108 colonyforming units (CFU) per mL and labeled as the stock suspension. Anadditional 1:10 dilution of the stock suspension is made using PBS toachieve a concentration of approximately 10⁵ to 10⁶ CFU per mL.

Neramexane mesylate (1 gram) is diluted into 9.0 mL of DI water toprepare a 10% solution (1:10 dilution). Then 5 mL is transferred into 11mL of DI water to prepare a 3.125% solution. This solution is theninoculated with the microorganism and tested at time intervals of 30seconds, 1 minute, and 5 minutes.

One milliliter from each dilution is spread plated in duplicate ontotryptic soy agar with 5% sheep blood. The plates are incubatedanaerobically at 35.2±2.5° C. for a minimum of 48 hours. The sameprocedure is repeated for the Phosphate Buffer Saline control. After theincubation period, all plates are counted to determine the number ofmicroorganisms remaining at each time point.

The concentration of each microorganism for the control and product iscalculated for each interval. The log reduction is calculated todetermine the change (reduction or increase) of the microorganismpopulation relative to a starting inoculum. The minimum requiredbactericidal concentration is defined as a 3 log reduction from theinitial inoculum. The results are shown in Table 20.

TABLE 20 Concentration of Exposure Organism (CFU/mL) % Reduction LogReduction Time Control Product Control Product Control Product Initial2.1E+05    2.1E+05 N/A N/A N/A N/A 30 sec 1.6E+05    1.8E+04 23.8  91.60.1 1.1  1 min 1.6E+05    4.4E+04 23.8  79.0 0.1 0.7  5 min 1.5E+05 <1028.6 100.0 0.1 4.3

Results

Based on the activity measured in the log reduction experiment,Neramexane exhibits antibacterial activity against Propionibacteriumacnes. These results indicate that neramexane may be useful in thetreatment of inflammatory skin diseases such as acne, rosacea, eczema,atopic dermatitis, psoriasis and oily skin.

Example 4 Local tolerability of topical Neramexane formulation

The objective of this study is to evaluate the local tolerance ofNeramexane mesylate in a topical formulation at different dose levelsafter 14 days of daily dermal treatment to minipigs.

The study is performed in 4 female Göttingen SPF minipigs (fromEllegaard Göttingen Minipigs Aps). Each animal has 5 application sites(25 cm²) marked on the back and is dosed for 8 hours each day. Each testsite is used for the same test item or placebo throughout the study. Thetest group is treated with Neramexane mesylate at the followingconcentrations: 0, 0.5, 2.5, 5.0 and 10.0% (w/w).

Clinical signs are recorded 2-4 hours post start of each treatment andthe local dermal reactions (erythema, oedema) are evaluated prior totreatment. Body weight is recorded weekly (and also on Day 1 and atnecropsy). Gross necropsy is performed on all animals, however nomacroscopic changes are observed and therefore only the dermalapplication sites are collected and subsequently macroscopically andmicroscopically histopathological evaluation is performed.

No test item related changes are observed in relation to clinical signsand body weight gain of the animals. Furthermore, no test item relateddermal skin reactions are observed throughout the study. The resultsfrom the histopathology evaluation of the dermal applications sitesreveals no treatment-related macroscopic or microscopic findings ascompared to the untreated skin samples.

In conclusion, dermal treatment of Göttingen minipigs for 14 Days withNeramexane mesylate at dose levels of and 0.5%, 2.5%, 5% and 10% in atopical formulation results in no test item related changes. Under theconditions of this study, the Neramexane topical formulationdemonstrates a good local (topical) tolerability.

Example 5 Anti-Microbial Potency of Neramexane Against RelevantBacterias—Determination of MIC and MBC Values by the Agar DilutionMethod

To assess the anti-microbial potency of Neramexane against acne relevantbacterias the minimal inhibitory concentration (MIC) and minimalbactericidal concentration (MBC) against the following bacterias isestablished:

1. Staphylococcus epidermidis ATCC 12228 2. Propionibacterium acnes ATCC11828 3. Propionibacterium granulosum ATCC 11829 4. Propionibacteriumavidum ATCC 25577

Procedure

The MICs of the samples are determined using the agar dilution methodbased on DIN 58940. Petri dishes of 5.5 cm diameter are poured with 2.5ml of freshly prepared Mueller-Hinton agar (Merck company, Cat-No1.05437) or Wilkins-Chalgren-Agar (Oxoid company, Cat-No CM643),maintained in liquid form at 50° C., to which the sample dilutions atvarious concentrations have been added at 50.0 vol.-%.

Preparation of Test Solution and Agar Plates

For the different test compounds the following concentration ranges aretested:

Testing Testing product Concentration product no. name range [%] 1.Neramexane- 6.25 − 1*10⁻² Mesylate 2. Neramexane-HCl 1.56 − 2*10⁻³

To prepare the starting sample dilutions, a 12.5%, 3.12% suspension ofthe respective sample solution is prepared with Aqua purificata. Fromthese stock-solutions, further dilutions are prepared with Aquapurificata. All test compounds are adjusted to pH 5.5. For test productno. 1, separate dilutions adjusted to pH 6.0 and pH 7.4 are alsoprepared.

Execution of the Agar Dilution Test

For inoculation, 1 μl of the respective germ suspension is placed on thecentre of each agar plate. After drying, inoculated plates are incubatedat 36.0±2.0° C. The basis for the length of incubation period is therespective growth control cultivated in parallel.

TABLE 21 Test Organisms and Microbial Counts of Test Microbe SuspensionsNo Test Organisms CFU*/ml 1 Propionibacterium acnes ATCC 11828 2.6 × 10⁸2 Propionibacterium avidum ATCC 25577 3.0 × 10⁸ 3 Propionibacteriumgranulosum ATCC 11829 3.9 × 10⁸ 4 Staphylococcus epidermidis ATCC 122281.9 × 10⁷ *= colony forming units

The purity and identity of all test microorganisms is checked bypreparation of subcultures on Columbia-Blood agar for germs no. 1-3(anaerobic) and germ no. 4 (aerobic). Subsequently, the germs areidentified by determination of the biochemical profile using ATB/API.

The test microbe suspension is prepared by inoculating a few individualcolonies of the respective bacteria into sterile saline solution until aturbidity corresponding to the McFarland standard 1.0 (approximately 10⁸cfu/ml) is reached. After that, the test microbe suspensions are furtherdiluted 1:10 with saline solution and the microbial counts (see Table21) are determined by the surface spread method using a spiral plater.

The agar plates are incubated under the conditions given in Table 22 andsubsequently evaluated. The MIC-values as given represent the lowestconcentration of the active substance at which there is nomacroscopically visible growth. Minimal, barely visible growth or fewsmall individual colonies are evaluated as inhibition.

TABLE 22 Inoculation and Incubation Conditions Test Growth Organism NoConditions Nutrient Medium Incubation 1-3 anaerobic Wilkins-Chalgren16-20 h at agar 36° C. 4 aerobic Mueller-Hinton 16-20 h at agar 36° C.

Determination of the Minimal Bactericidal Concentration (MBC)

All negative tests of the determination of the minimal bactericialconcentration are the basis of verification of remaining germs, theinoculated agar segments are cut and put in Mueller-Hinton-Bouillon(germ 1) or Wilkins-Chalgren-Bouillon (germs 2-4). After an adequateincubation period at 36.0±2.0° C. (as judged from a control without testcompound), the tests are checked manually on microbial growth(=turbidity) and the minimal bactericidal concentration is determined.MBC indicates the concentration without marked turbidity. Grown germsare checked for identity to rule out unspecific contaminations.

Evaluation of Data

The following results are summarized and tabulated:

a) Results of the Minimal Inhibitory Concentration (MIC)* b) Results ofthe Minimal Bactericidal Concentration (MBC)

* The MIC is the concentration without macroscopical growth. Scarcelyapparent, minimum growth or few single colonies are not considered. Thecontrols must have a respectively good developed growth. There must beno growth on the agar plates for the sterile control.

The results for the individual test-compounds are shown in Tables 23-30.These tables summarize the determined MIC and MBC-values for the testedgerms in the last column.

The growth of bacteria is indicated for the duplicate plates by a +(i.e., growth) or a − (i.e., no growth), +− indicates weak growth onboth plates or growth on one plate and no growth on the other plate. Allbacteria show appropriate growth on the respective control plate notcontaining any test compound. No influence of the used diluent (Aquapurifacata) was observed. No contamination is observed on thecontrol-plates.

TABLE 23 MIC values for Neramexane-Mesylate at pH 5.5 FinalConcentration (%) MIC in 6.25 3.13 2.50 1.56 0.63 0.31 0.16 0.08 0.040.01 (%) Propionibacterium − − − − − − − − − − − − − − − − + + + + 0.08acnes Propionibacterium − − − − − − − − − − − − − − − − + + + + 0.08avidum Propionibacterium − − − − − − − − − − − − − − − − + + + + 0.08granulosum Staphylococcus − − − − − − − − − − − − − − + + + + + + 0.16epidermidis

TABLE 24 MBC values for Neramexane-Mesylate at pH 5.5 FinalConcentration (%) MBC 6.25 3.13 2.50 1.56 0.63 0.31 0.16 0.08 in (%)Propionibacterium − − − − − − − − + + + + + + + + 1.56 acnesPropionibacterium − − − − − − − − − − + + + + + + 0.63 avidumPropionibacterium − − − − − − − − − − + + + + + + 0.63 granulosumStaphylococcus − − − − − − − − + + + + + + not 1.56 epidermidis tested

TABLE 25 MIC values for Neramexane-Mesylate at pH 6.0 FinalConcentration (%) MIC in 6.25 3.13 2.50 1.56 0.63 0.31 0.16 0.08 0.040.01 (%) Propionibacterium − − − − − − − − − − − − − − − − + + + + 0.08acnes Propionibacterium − − − − − − − − − − − − − − − − + − + + 0.08granulosum

TABLE 26 MBC values for Neramexane-Mesylate at pH 6.0 FinalConcentration (%) MBC 6.25 3.13 2.50 1.56 0.63 0.31 0.16 0.08 in (%)Propionibacterium − − − − − − − − − − + + + + + + 0.63 acnesPropionibacterium − − − − − − − − − − − − + + + + 0.31 granulosum

TABLE 27 MIC values for Neramexane-Mesylate at pH 7.4 FinalConcentration (%) MIC in 6.25 3.13 2.50 1.56 0.63 0.31 0.16 0.08 0.040.01 (%) Propionibacterium − − − − − − − − − − − − − − + + + + + + 0.16acnes Propionibacterium − − − − − − − − − − − − − − − − + − + + 0.08granulosum

Table 28 MBC values for Neramexane-Mesylate at pH 7.4 FinalConcentration (%) MBC 6.25 3.13 2.50 1.56 0.63 0.31 0.16 0.08 in (%)Propionibacterium − − − − − − − − + + + + + + not 1.56 acnes testedPropionibacterium − − − − − − − − + + + + + + + + 1.56 granulosum

TABLE 29 MIC values for Neramexane-HCl at pH 5.5 Final Concentration (%)MIC in 1.56 0.63 0.31 0.16 0.08 0.04 0.02 0.01 0.005 0.002 (%)Propionibacterium − − − − − − − − + + + + + + + + + + + + 0.16 acnesPropionibacterium − − − − − − − − + − + + + + + + + + + + 0.16 avidumPropionibacterium − − − − − − − − − − + + + + + + + + + + 0.08granulosum Staphylococcus − − − − + + + + + + + + + + + + + + + + 0.63epidermidis

TABLE 30 MBC values for Neramexane-HCl at pH 5.5 Final Concentration (%)MBC in 1.56 0.63 0.31 0.16 0.08 (%) Propionibacterium − − + + + + + +not 1.56 acnes tested Propionibacterium − − + + + + + + not 1.56 avidumtested Propionibacterium − − − − + + + + + + 0.63 granulosumStaphylococcus + + + + not not not >1.56 epidermidis tested testedtested

Results

Table 31 summarizes the MIC and MBC values for all test-compounds asestablished in this study. In general it has to be considered thatvalues determined by the used method can vary by a factor of 2 (for 1:2dilutions).

TABLE 31 Summary of determined MIC and MBC values (given in %) P. acnesP. avidium P. granulosum S. epidermidis Compound MIC MBC MIC MBC MIC MBCMIC MBC Neramexane- 0.08 1.56 0.08 0.63 0.08 0.63 0.16 1.56 Mesylate pH5.5 Neramexane- 0.08 0.63 not not 0.08 0.31 not not Mesylate testedtested tested tested pH 6.0 Neramexane- 0.16 1.56 not not 0.08 1.56 notnot Mesylate tested tested tested tested pH 7.4 Neramexane- 0.16 1.560.16 1.56 0.08 0.63 0.63 >1.56 HCl pH 5.5

Neramexane exhibits antibacterial activity with respect to allacne-relevant bacterias tested. Within the range of this assay theestablished MIC values and MBC values at the skin relevant pH 5.5 arecomparable for the different bacteria-strains. Thus, Neramexanedemonstrates similar efficacy against all tested bacterias.

There is also no obvious effect of the pH on this anti-bacterialactivity. The MIC and MBC values established at pH 6.0 and pH 7.4 arewithin the same range as those established at pH 5.5. The same holdstrue for the MIC and MBC-values obtained with Neramexane-HCl. With theexception of values for S. epidermidis, these values differ max. by afactor 2 from those obtained with Neramexane-Mesylate. These datademonstrate that the salt-form of the active has minor impact on theanti-bacterial activity of Neramexane.

Thus, the observed anti-bacterial activity towards acne relevantbacterias is a property of Neramexane as such.

Example 6 Anti-Microbial Potency of Neramexane Against RelevantBacterias—Determination of Bactericidal Activity in a QuantitativeSuspension Assay

To further assess the anti-microbial potency of Neramexane aquantitative suspension assay is performed.

Procedure

1.0 ml of the bacterial test suspension (microbial count: 1.5−5.0×10⁸cfu/ml) and 1.0 ml distilled water is added to 8.0 ml of the producttest solution. The stopwatch is started. At the end of the exposuretime, 0.1 ml of the test mixture is added to 50 ml rinsing liquid (=testneutralization mixture, TNM, 10°). Two dilutions of the TNM are preparedby pipetting 500 μl of TNM to 9.0 ml of tryptone-NaCl (represents adilution 10⁻² of TNM before filtration) resp. 50 μl of TNM to 9.0 ml oftryptone-NaCl (represents a dilution 10⁻³ of TNM before filtration). TheTNM (in duplicate) and each of the dilutions are transferred to amembrane filter device fitted with a membrane filter (0.45 μm) andfiltered immediately. Subsequently, the filter is washed with 150 mldistilled water. The membranes are transferred to agar plates. Afterincubation under appropriate conditions, colonies are counted andreported.

Neramexane-mesylate is tested at 4 different concentrations (w/w 0.1%,0.5%, 2.0%, 5.0%) to assess its bactericidal activity againstPropionibacterium acnes (ATCC 11828). In addition to the effect of theconcentration of Neramexane, the relevance of the contact time with thebacterias is assessed at 4 different incubation times (5 min, 30 min, 6h, 24 h).

After the desired incubation time, the complete elimination of the testcompound from the assay is ensured by membrane filtration. Bacterialsuspensions with a microbial count ranging from 1.5−5.0×10⁸ cfu/ml areused. All assays are performed at the skin relevant pH of 5.5.

The read out is reduction of the bacterial number in the assay,expressed as log-reduction. This reduction of the bacterial count iscorrelated to the ability of a compound to kill the bacteria, thus,corresponding to its MBC value. A >5-fold log reduction is required fora surface-disinfection compound and a >3-fold log reduction for ahand-disinfection compound.

Results

A summary of the results for Neramexane-mesylate is shown in Table 32.

TABLE 32 Summary of log-reduction values for Neramexane-mesylateConcentration/ Contact time 5 min 30 min 6 h 24 h 0.1% <1.41 <1.41 <1.41<1.41 0.5% <1.41 <1.41   2.60 >5.48 2.0% <1.41 >5.48 >5.48 >5.48 5.0%  4.33 >5.48 >5.48 >5.48

A concentration of 0.5% efficiently eliminates P. acnes in this assayafter 24 h contact time. Even after 6 h contact a significantlog-reduction (2.6-fold) is obtained. With a 2.0% solution, the maximumreduction within this assay of >5-fold log-reduction is reached afteronly 30 min incubation. With a 5% solution, a log-reduction of 4.33-foldwas obtained after only 5 min incubation.

These data confirm that Neramexane efficiently eliminates the acnerelevant P. acnes bacteria in suspension. Depending on theconcentration, only a short incubation time is necessary to demonstratethis antimicrobial activity.

Example 7 Anti-Microbial Potency of Neramexane Against Streptococcuspyogenes and Staphylococcus aureus—Determination of MIC Values by theAgar Dilution Method

To assess the anti-microbial potency of Neramexane against bacteriastrains which are relevant for atopic dermatitis and localized skininfections (“impetigo”), the minimal inhibitory concentration (MIC)against the following bacteria is established:

5. Staphylococcus aureus ATCC 6538 6. Streptococcus pyogenes ATCC 12344

While infections with Staphylococcus aureus is a very commoncomplication in atopic dermatitis the same bacteria-strain is alsoinvolved in localized skin infections (“impetigo”) together withStreptococcus pyogenes.

Procedure

The MICs of the samples are determined using the agar dilution methodbased on DIN 58940. Petri dishes of 5.5 cm diameter are poured with 2.5ml of freshly prepared Mueller-Hinton agar 2-fold concentrated (Merckcompany, Cat-No 1.05437), pH 5.5, maintained in liquid form at 50° C.,to which the sample dilutions at various concentrations has been addedat 50.0 vol.-%.

Preparation of Test Solution and Agar Plates

Neramexane-Mesylate is tested in the concentration range of6.25−1*10⁻²%. All test solutions are adjusted to pH 5.5.

Execution of the Agar Dilution Test

For inoculation, 1 μl of the respective germ suspension is placed on thecentre of each agar plate. After drying, inoculated plates are incubatedat 36.0±2.0° C. The basis for the length of incubation period is therespective growth control cultivated in parallel.

TABLE 33 Test Organisms and Microbial Counts of Test Microbe SuspensionsNo Test Organisms CFU*/ml 1 Staphylococcus aureus ATCC 6538 3.4 × 10⁷ 2Streptococcus pyogenes ATCC 12344 3.6 × 10⁷ *= colony forming units

The test microbe suspension is prepared by inoculating a few individualcolonies of the respective bacteria into sterile saline solution until aturbidity corresponding to the McFarland standard 1.0 (approximately 10⁸cfu/ml) is reached. After that, the test microbe suspensions are furtherdiluted 1:10 with saline solution and the microbial counts (see Table33) are determined by the surface spread method using a spiral plater.

The agar plates are incubated under the conditions given in Table 34 andsubsequently evaluated. The MIC-values as given represent the lowestconcentration of the active substance at which there is nomacroscopically visible growth. Minimal, barely visible growth or fewsmall individual colonies are evaluated as inhibition.

TABLE 34 Inoculation and Incubation Conditions Test Organism GrowthNutrient No Conditions Medium Incubation ½ Aerobic Mueller-Hinton 16-20h at 36° C. agar

Evaluation of Data and Results

The results for the individual test-compounds are shown in Tables 35.The growth of bacteria is indicated for the duplicate plates by a +(i.e., growth) or a − (i.e., no growth), +− indicates weak growth onboth plates or growth on one plate and no growth on the other plate.Both bacteria-strains show appropriate growth on the respective controlplate not containing any test compound. No influence of the used diluent(Aqua purifacata) is observed. No contamination is observed on thecontrol-plates. In general it has to be considered that valuesdetermined by the used method can vary by a factor of 2 (for 1:2dilutions).

TABLE 35 MIC values for Neramexane-Mesylate at pH 5.5 FinalConcentration (%) MIC in 6.25 3.13 2.50 1.56 0.63 0.31 0.16 0.08 0.040.01 (%) Staphylococcus − − − − − − − − + − + + + + + + + + + + 1.56aureus Streptococcus − − − − − − − − − − − − − − − − + + + + 0.08pyogenes

Neramexane exhibits antibacterial activity with respect toStaphylococcus aureus which is relevant for atopic dermatitis and theskin disease impetigo contagiosa and acts even to greater extend againstStreptococcus pyogenes, which is also involved in impetigo contagiosa.

The used agar dilution assay is a standard assay for establishing theantibacterial potential of a test compound. The growth conditions andinoculated number of bacteria avoid an overestimation of theanti-bacterial effect of a test-compound. The chosen skin relevant pH of5.5 further promotes the generation of data which are relevant fortreatment of skin associated bacterial infections. The obtained data arethus adequate for determination of the therapeutic antibacterialpotential of Neramexane against both bacterial strains.

Therefore these data allow predication of the therapeutic use ofNeramexane in indications with involvement of the testedbacterial-strains.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

All patents, applications, publications, test methods, literature, andother materials cited herein are hereby incorporated by reference.

We claim:
 1. A method of treating or preventing inflammatory skindiseases in a subject in need thereof, comprising administering aneffective amount of a 1-amino-alkylcyclohexane derivative selected fromneramexane and pharmaceutically acceptable salts thereof.